Journal Club: Genetics, Virology, Immunology, and Pharmacology

Graduate Division

GENETICS: Expression of the TEL-Syk fusion protein in hematopoietic stem cells leads to rapidly fatal myelofibrosis in mice. Graham, M.T.; Abram, C.L.; Hu, Y.; Lowell, C.A. PLoS One. 8(10):e77542.

Some cancers arise from common “mistakes” in cellular division: Certain regions of our chromosomes are statistically more likely to break, and when they accidentally rejoin in the wrong place, they can generate fusion proteins (proteins that are the result of two genes getting accidentally stuck together) of products that when mutated, cause the cell to uncontrollably divide more.

Other cancers have more elusive causes. In this paper, researchers extensively characterized the causative mutation behind a patient’s leukemia. Cells isolated from the patient were found to have a fusion protein of TEL and Syk, which resulted in constitutive activation of the transcription factor STAT5 when the mutant gene was transformed into cells in vitro.

When these transformed cells were implanted into mice, it was lethal in about two months. Mice showed significant early myeloexpansion (cell overgrowth), followed by extensive liver and spleen fibrosis and damage, leading to death.

VIROLOGY: HIV-associated disruption of mucosal epithelium facilitates paracellular penetration by human papillomavirus. Tugizov, S.M. et al. (Palefsky) Virology. 446(1-2):378-88.

Human papilloma virus (HPV) is much more common in HIV-infected individuals than non-infected individuals. Here, researchers wanted to determine whether this association was biological in nature, by testing whether HIV-infected tissues are more susceptible to infection with HPV.

Expression of the HIV proteins tat and gp120, which can be found in HIV-infected mucosa, is known to compromise the expression of tight junctions between epithelial cells, which is a primary defense against infection with invasive pathogens.

To test this phenomenon experimentally, the researchers added tat and gp120 to in vitro cultures of polarized epithelial cells. Indeed, they found that the tight junctions were compromised when exposed to the HIV proteins, but they also found that HPV virions were able to penetrate deeper into the polarized epithelial layers when the tight junctions were compromised.

IMMUNOLOGY: Deletion of the activating NKG2C receptor and a functional polymorphism in its ligand HLA-E in psoriasis susceptibility. Zeng, X.; Chen, H.; Gupta, R.; Paz-Altschul, O.; Bowcock, A.M.; Liao, W. Experimental Dermatology. 22(10):679-681.

Psoriasis is a skin disease characterized by rough, scaly patches of skin that is caused by an overgrowth of skin cells, which is thought to be due to immune system dysregulation.

NK cells, which can respond to a variety of pathogens by killing infected cells, have long been suspected of playing a role in the disease — though the exact process by which they contribute to psoriasis has so far proved elusive.

Here, researchers performed a population study on Caucasians to see whether there were correlations between certain alleles or mutations in NK-cell related genes and psoriasis.

Perhaps counter-intuitively, they found that deletions in the activating NKG2C receptor on NK cells correlated positively with psoriasis, and they found additional susceptibility with a low-expressing allele for HLA-E.

The researchers conclude that without the activating NK receptor NKG2C, NK cells may not be able to inhibit self-reactive, potentially psoriasis-causing T-cells as efficiently, thereby contributing to disease.

PHARMACOLOGY: Epoxyeicosatrienoic acids prevent Cisplatin-induced renal apoptosis through a p38 MAPK regulated mitochondrial pathway. Liu, Y. et al. (Kroetz). Molecular Pharmacology. October 3. [Epub ahead of print]

Cisplatin is a commonly used, often life-saving chemotherapy used for a variety of solid tumors. Like most chemotherapeutic agents, however, the drug has significant toxicity issues: Cisplatin, in particular, tends to cause kidney failure due to tubule cell death.

Many cellular pathways contribute to the tubule cell death, and it was thought that if some of those pathways could be inhibited,  cell death due to chemotherapy treatment could perhaps be limited, helping to reduce serious side-effects of treatment.

Recently, this research group found that epoxyeicosatrienoic acid (EET) levels are increased by inhibition of soluble epoxide hydrolase (sEH), which has been proposed to treat renal disease.

Here, the group found that inhibition of sEH prevented apoptosis of kidney cells treated with cisplatin by preventing mitochondrial damage and reactive oxygen species formation in the cell, which was also corroborated by adding extra EETs to kidney cells treated with the drug.

The authors conclude that sEH inhibition may be a novel therapeutic strategy to prevent cisplatin toxicity during cancer treatment.